Beyond Hemoglobin Concentration: How Intravascular Volume Measurements Can Advance Our Understanding of High‐Altitude Adaptation

Hemoglobin concentration is often interpreted as a marker for total hemoglobin mass in studies investigating high-altitude adaptation. However, hemoglobin concentration is determined by both plasma volume and total hemoglobin mass. Therefore, using hemoglobin concentration as a marker for hemoglobin mass can obscure variation in total hemoglobin mass and/or plasma volume and lead to flawed conclusions about adaptation. In this short commentary, we highlight examples from athletic, clinical and high-altitude populations and responses to environmental stressors illustrating the dissociations between intravascular volumes and hemoglobin concentration. The reliance on hemoglobin concentration has reinforced the prevailing, but potentially incorrect, interpretation of blunted hypoxia-induced erythropoiesis in Tibetan and Ethiopian highlanders. We argue that measures of plasma volume and total hemoglobin mass, which can easily be obtained using the carbon monoxide rebreathing technique, provide more physiologically relevant phenotypes. We propose that future genetic and evolutionary studies of high-altitude adaptation should move beyond hemoglobin concentration and focus on measurements of total hemoglobin mass and intravascular volumes.